Therapeutic compositions comprising 5-amino hexahydropyrimidines or salts thereof



United States 2,837,463 THERAPEUTIC coMrosrrroNs COMPRISING S-AMINOHEXAHYDROPINES OR SALTS THEREOF No Drawing. Application January 10, 1958Serial No. 708,072

21 Claims. (Cl. 167-93) This invention relates to therapeuticcompositions and atent more particularly to therapeutic compositionscontaining certain S-amino hexahydro pyrimidine compounds.

This application is a continuation-in-part of our copending applicationsSerial No. 393,247, filed November 19, 1953, now abandoned, Serial No.447,408, filed August 2, 1954, now abandoned, and Serial No. 547,332,filed November 16, 1955, now abandoned.

Briefly, the present invention is directed to therapeutic compositionscomprising a compound having the formula: H:

C RN NR \C 111 \NH: wherein R is an alkyl, aryl, aralkyl, alkaryl,hydroxyalkyl, aminoalkyl or cycloalkyl radical and R is hydrogen, or alower alkyl or hydroxymethyl radical, and a pharmaceutical carrier. Inlieu of employing the above -amino-hexahydropyrimidines in the form oftheir free bases, the salts of these amine compounds may also beutilized.

Among .the several objects of the invention may be noted the provisionof therapeutic compositions which are effective for various therapeuticpurposes including, for example, the treatment of bovine mastitis, skininfections, fungus infections, scalp infections and other infections,both surface and systemic, caused by microorganisms; the provision oftherapeutic compositions which are effective, for example, to inhibitthe growth of microorganisms for which vitamin B is an essentialmetabolite or growth factor and certain enzyme systems in whichcocarboxylase functions as an essential part; the provision oftherapeutic compositions which are suitable, for example, forintroduction into the oral cavity and for topical application to theskin and for parenteral administration; and the provision 'oftherapeutic compositions of the class described which are nontoxic,nonsensitizing, nonirritating, and stable. Other objects and featureswill be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the products hereinafter described,the scope of the invention being indicated in. the following claims.

In accordance with the present invention, it has now I been found thatcompositions including a S-amino-hexahydropyrimidine compound having thefollowing formula:

2,837,463 Patented June s, 1958 wherein R is an alkyl, aryl, aralkyl,alkaryl, hydroxyalkyl, aminoalkyl or cycloalkyl radical and R representshydrogen or a lower alkyl or hydroxymethyl radical and the saltsthereof, are useful therapeutic compositions for various applications.For example, we have found that the growth and development ofmicroorganisms for which vitamin B is an essential metabolite or growthfactor and the activity of certain enzyme systems in which cocarboxylaseis an essential component can be effectively inhibited by the use of thenovel therapeutic compositions of the present inventtion.

It is known that vitamin B is an essential metabolite, i. e., anecessary constituent of the normal metabolic processes, and growthfactor for many microorganisms. The presence of the coenzyme,cocarboxylase, which is a crystalline diphosphoric acid ester of vitaminB is required in order for the enzyme carboxylase to remove carbondioxide from pyruvic acid and other organic acids formed fromcarbohydrates in the metabolism of such microorganisms. Accordingly, inthe presence of vitamin 13,, the microorganisms grow and developnormally through the energy derived from the metabolic process describedabove.

Without limiting in any way the scope of the invention with respect tothe mode in which these novel therapeutic compositions operate when usedfor various therapeutic purposes, it is believed that theS-amino-hexahydropyrimidine component of the compositions of theinvention acts as an antimetabolite or competitive antagonist forvitamin B in the metabolism of the microorganisms. TheS-amino-hexahydropyrimidine component is believed to form a complex withthe enzyme carboxylase which, unlike the complex formed in the case ofvitamin B is incapable of effecting the chemical changes characteristicof those occurring in the presence of cocarboxylase. Consequently, thedecarboxylation of pyruvic acid, for example, as well as other organicacids ceases and the growth and development of. the microorganisms arethereby inhibited because of this interruption of their normal metabolicprocesses. Likewise, the compositions of the present invention areeffective against certain enzyme systems of which cocarboxylase is anessential component.

The compositions of the invention are markedly eflective in inhibitingthe growth of microorganisms for which vitamin B is an essentialmetabolite or growth factor. 1

The measurement of antagonism between metabolite and antimetabolite maybe expressed by a number known as the inhibition index. The inhibitionindex is the quotient of the ratio of concentration of the twosubstances at which their effects are just counterbalanced, andrepresents the amount of antimetabolite which is needed to overcome theeffect of a unit weight of metabolite. Thus, a low inhibition index isindicative of the high effectiveness of an antimetabolite. Theinhibition index in the case of vitamin B and theS-amino-hexahydropyrimidine compounds included in the compositions ofthe present invention is relatively low, and therefore, in general, itmay be stated that ,only relatively small amounts of these compositionsare required to offset the effect of relatively large amounts of vitaminB And since the antagonism between these pyrimidine compounds andvitamin B is competitive, the inhibition index is relatively constantwith respect to all microorgan isms for which vitamin B is an essentialmetabolite.

Among the many microorganisms against which the compositions of theinvention are effective may be menorganisms isolated from acute andchronic bovine mastitis cases. Further, under therapeutic conditionsinduction of resistance in microorganisms to the compositions of theinvention has not been found.

The therapeutic compositions of the invention are useful and effectivein various therapeutic applications including, for example, thetreatment of bovine mastitis, skin infections, fungus infections such asathletes foot, scalp infections, vaginal infections, nose and throatinfections and other infections caused by microorganisms for whichvitamin B is an essential metabolite or growth factor.

Where the compositions of the invention are employed for dentalpurposes, their introduction into the oral cavity reduces acid formationon the tooth surface for prolonged periods of time and operates tomaintain the pH well above the value of approximately 5.2. It isbelieved that the pyrimidine compound component of these therapeuticcompositions operates by being effectively retained on dental plaquesand, therefore, remains available over sustained periods of time toreduce acid production. These therapeutic compositions will exert asufficiently persistent action in reducing acid production to beeffective under the conditions of morning and evening use.

The pyrimidine compounds specified herein are not only compatible withother components employed in therapeutic compositions, but they are alsostable, nontoxic, nonirritating and nonsensitizing. For example, the

LD (a standard statistical value which corresponds to the single dosewhich is lethal to 50% of the test animals) for the compound1,3-bis(beta-ethylhexyl)-5-methyl-S-amino-hexahydropyrimidine is 1630mg./kg. orally in rats and 142 mg./kg. intraperitoneally in mice. Themaximum daily tolerated dose of this exemplary pyri midine compound inthe rate is 75-l00 mg./kg. Three groups of twenty rats each were given0.02%, 0.05% and 0.1% by weight of l,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine in their diet for a period of forty-eightweeks. No mortalities were observed in any of the three groups.Histopathology of these animals at six months showed no pathologicallesions attributed to l,3-bis(beta-ethylhexyl)-5-methyl-5-arnino-hexahydropyrimidine. Further, repeated instillationof a saturated aqueous solution of 1,3-bis(beta-ethylhexyl)-S-methyl-5-amino-hexahydropyrimidine into rabbits eyes showed that this exemplarypyrimidine compound is not a primary irritant to delicate tissues.

The pyrimidine compounds of these novel therapeutic compositions havethe formula:

wherein R is an alkyl, aryl, aralkyl, alkaryl, hydroxyalkyl, aminoalkylor cycloalkyl radical and R is hydrogen, or a lower alkyl orhydroxymethyl radical. These compounds may be prepared by the methoddescribed in U. S. Patent 2,387,043. Among theS-amino-hexahydropyrimidine compounds which have been found elfectivcmay be mentioned l,3-bismethyl-5-methyl-5-amino-hexahydropyrimidine,1,3-bis(beta-ethylhexyl -5-methyl-5-amine-hexahydropyrimidine,l,3-bispropyl-S-rnethyl-S-amino-hexahydropyrimidine,1,3-bisisopropyl-5-methyl-S-amino-hexahydropyrimidine,l,3-bisbutyl-5-methyl-5-aminohexahydropyrimidine, 1,3-bis(second arybutyl)-5-methyl- 5-amino-hexahydropyrimidine, l,3-bis(tertiary butyl)-5'methyl-S-amino-hexahydropyrimidine, 1,3-bishexyl-5- methyl 5 aminohexahydropyrimidine, 1,3-bisheptyl- 5 -methyl-S-arnino-hexahydropyrirnidine, l ,3-bisocty1-5-methyl-5-amino-hexahydropyrimidine, 1,3-bisdecyl5methyl-5-amino-hexahydropyrimidine, l,3-bisdodccyl-5-methyl-S-amino-hexahydropyrimidine, 1,3-bistetradecyl-S-methyl-5-amino-hexahydropyrimidine, 1,3-bishexadecyl-5- methyl-5-amino-hexahydropyrimidine, 1,3-bis( 1 -methylheptyl-5-methyl-5-amino-hexahydropyrimidine, 1,3-bis (1,3 dimethylbutyl) 5methyl 5 amino hexahydropyrimidine, l,3-bis(tertiarybutyl-Z-methyl)-5methyl-5- amino-hexahydropyrimidine, 1,3-bis(isopropyl-Z-methyl S-methyl-amino-hexahydropyrimidine, 1,3-bis (hydroxytertiary butyl)-S-methyl-S-amino-hexahydropyrimidine, l, 3bis(isopropyl) 5 hydroxymethyl 5 amino hexahydropyrimidine, 1 ,3-bisfi-hydroxyethylaminopropyl) -5- methyl-5-amino-hexahydropyrimidine,l,3-bis( 1,1-dimethyl 2 hydroxyethyl) 5 methyl 5 aminohexahydropyrimidine,l,3-bis(butylaminopropyl)-5-methyl-5-amino-hexahydropyrimidine, 1 ,3-bis(beta-ethylhexyl) -5-amino-hexahydropyrimidine, 1-,3-bis(beta-ethylhcxyl) -5 hydroxymethyl-S-amino-hexahydropyrimidine, 1,3-bis(cyclohexyl)-5methyl-S-amino-hexahydropyrimidine, 1,3- bis(dicyclohexyl)5 methyl 5 amino hexahydropyrimidine,1,3-bistolyl-5methyl-5-amino-hexahydropyrimidine,1,3-bisbenzyl-5-methyl-Samino-hexahydropyrimh dine, l ,3-bis(methylbenzyl) -5 -methyl-S-amino-hexahydropyrimidine,1,3-bisphenyl-5-methyl-5-amino-hexahydropyrimidine, 1 ,3-bis(phenylethyl) -5-methyl-5-amino-hexahydropyrimidine, 1,3-bis(beta-ethylhexyl) -5-ethyl-5-amino-hexahydropyrirnidine,l,3-bis-dodecyl-5-cthyl-5-aminohexahydropyrimidine, l,3-bis(hydroxytertiary butyl)-5- ethyl-5-amino-hexahydropyrimidine,1,3-bis(beta-ethylhexyl)-5-propyl-S-amino-hexahydropyrimidine, and 1,3-bis(beta ethylhexyl) 5 butyl 5 amino hexahydropyrimidine. It will beunderstood that other S-aminohexahydropyrirnidine compounds of theabove-noted classes are also suitable for use in the compositions of theinvention.

As stated above, in lieu of employing the S-aminohexahydropyrimidinesabove in the form of their free.

bases, the salts of these amine compounds may also be utilized. Saltsare readily formed with acids such as, for example, acetic acid,phosphoric acid, boric acid, hydrochloric acid, maleic acid, benzoicacid, citric acid, malic acid, oxalic acid, tartaric acid, succinicacid, glutaric acid, gentisic acid, Valerie acid, gallic acid,,S-resorcylic acid, acetyl salicylic acid and salicylic acid, as well asperchloric acid, barbituric acid, sulfanilic acid, phytic acid andp-nitro benzoic acid. These amines also form useful salts with longchain aliphatic acids such as stearic acid, palmitic acid, oleic acid,myristie acid, and lauric acid. The trihydrochloride, for example, ishighly water soluble.

The therapeutic compositions of the present invention comprise apyrimidine compound of the class described above and a pharmaceuticalcarrier which may be either a liquid or solid material. When used fordental purposes, these compositions include not only paste, powder andliquid dentifrices, but also mouthwashes, chewing gum, tablets, lozengesand troches. For other uses, these compositions include water washableointments, non-water washable ointments, ophthalmic ointments, scalplotions, nasal preparations including nasal jellies, nasal sprays andnasal drops, aerosols (for topical application in the treatment offungi, for example), powders including foot powders and insufilationpowders tablets and vaginal preparations including vaginal suppositoriesand suitable compositions for parenteral administration. Examples ofsolid pharmaceutical carriers include starch, gelatin, lactose, talc,boric acid and the like. Any of the conventional pharmaceutical carriersused in pharmaceutical practice may be utilized herein where suchmaterials are compatible with the aforementioned pyrimidine compounds.These novel compositions may include a liquid pharmaceutical carrier andbe in the form of solutions, dispersions, suspensions and the like.Although these pyrimidine compounds are relatively insoluble in water,

they may be readily dispersed in any surface active agent which is asolvent for the pyrimidine compounds or in any such agent, which, whenadded to water, gives a semi-' colloidal solution, for example,ethanolamine salts, polyvinylpyrrolidone and the complex sorbitoletherester sold under the trade-designation Tween 20 are satisfactorydispersing agents. Also, these pyrimidine compounds are soluble in oilssuch as peanut oil and organic solvents.

The percentage of the pyrimidine compound incorporated in thetherapeutic compositions of the invention may be varied considerably,but we prefer to use an amount between approximately 0.01% by weight and1% by weight. Amounts smaller than 0.01% by weight of one of thepyrimidine compounds may also be used in the practice of the invention.

In addition to one of the above-noted pyrimidine compounds, the dentalcompositions of the invention may include a water-soluble oxalatecomponent, such as, for example, sodium, potassium and ammonium oxalatesand the urea salts of oxalic acid. The amounts of oxalate component,when included in these compositions may be varied considerably, but arange of approximately 0.25% to approximately 1.5% by weight ispreferred.

The following examples illustrate the invention.

Example 1 A dentifrice composition was prepared by mixing 99.5 parts byweight of a paste having the following components:

and 0.5 part by weight. of a concentrate having the followingcomponents:

Components: Percent by weight 1,3-bis(beta-ethylhexyl)-5methyl 5aminohexahydropyrimidine 20.0 Complex sorbitol ether-ester dispersingagent (sold under the trade designation Tween Water 40.0

The resulting product was a paste dentifrice composition containing 0.1%by weight of 1,3-bis(beta-ethylhexvl)-5-methyl-5-amino-hexahydropyrimidine.

Example 2 A dentifrice composition was prepared from the followingcomponents:

Components: Percent by weight Alumina hydrate 40.0 Example 10 7 Titaniumdioxide 1.0 Example was repeated employin 1,3-bis(beta-ethyl- Sodiumsaccharin 0.15 hexyl)-5-ethyl-S-amino-hexahydropyrimidine in a concen-Detergent 3.0 trationof 0.1 mg./ml. saliva. At this concentration, itGum tragacanth 1.5 was .found that 100% inhibition of acid formation wasSodium oxalate 0.5 65 attained. Glycerine 12.0 d-Sorbitol solutions 17.0Example 11 Phosphoric acid 5% 03 Ex mple 5 was repeated employing1,3-bisdodecyl-5- Flavor 5 ethyl-5-amino-hexahydropyrimidine in aconcentration of 1,3 bis(beta ethylhexyl) 5 methyl 70 0.1 mg./ml. sal iva At this concentration, it was found hexahydmpyrimidine 00333 that 100%inhibition of acid formation was attainedw 1 Complex sorbitolether-ester dispersing agent (sold under the trade designation TweenExample 12 v I 20") 0.0667 Example 5 was repeated employing1,3-bis(hydro xy Water (q. s. to 100%) 23.464 1 tertiary butyl) 5 ethyl5 amino hexahydropyrimi- Example 3 A dentifrice composition as describedin Example-12' was prepared except that 0.01% of1,3-bis(beta-ethylhexyl)-5 methyl-5-amino-hexahydropyrimidine wasemployed. The percentage by Weight of the water component was adjustedto compensate for the decreased percentage of the pyrimidine compound.

Example 4 A mouthwash was prepared from the following components:

Water q. s. 1000.00 ml. 7

Example 5 Thetechniques described in Fancher, O. E. Fosdick,

L. S., and Calandra, J. C., J. Dental Res. 23: 23 (1944),

Calandra, J. C., and Fosdick, L. S., J. Dental Res. 26: 303 1947), andCalandra, J. C., and Fosdick, L. S., J. Dental Res. 26: 309 (1947), wereemployed to determine acid formation in saliva-enamel-sugar mixtures.When tested by these techniques, 1,3-bis(cyclohexyl)-5-methyl-S-amino-hexahydropyrimidine in a concentration of 2 mg./ml.saliva was found to reduce acid formation. 2

Example 6 Example 5 was repeated employing 1,3-bisdodecy1-5-methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml.saliva. At this concentration, it was found that inhibition of acidformation was attained.

Example 7 Example 5 was repeated employing 1,3-bistetradecyl-5-methyl-5-amino hexahydropyrimidine in a concentration of 2 mg./ml.saliva. At this concentration, it was found that 100% inhibition of acidformation was at- I tained.

Example 8 Example 5 was repeated employing 1,3-bishexadecyl-5-methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml.saliva. At this concentration, it was found that 100% inhibition of acidformation was attained.

Example 9 Example 5 was repeated employing1,3-bis(dicyclohexyl)-5-methyl-S-amino-hexahydropyrimidine in aconcentration of 0.1 mg./ml. saliva. At this concentration, it was foundthat 100% inhibition of acid formation was attained.

7 dine in a concentration of 0.1 mg./m1. saliva. At this concentration,it was found that 100% inhibition of acid formation was attained.

Example 13 Example was repeated employing 1,3bis(cyclohexyl)-5-ethyl-5-amino-hexahydropyrimidine in a concentrationof 2 mg./ml. saliva. At this concentration, it was found that 100%inhibition of acid formation was attained.

Example 14 A therapeutic foot powder was prepared from the followingcomponents:

A water washable therapeutic ointment was prepared from the followingcomponents:

1,3 bis(beta-ethylhexyl) 5 methyl 5 -arninoheXahydro-pyrimidine gHydrophilic ointment (USP), q. s. to 100.0 g.

Example 16 A nonwater washable therapeutic ointment was prepared'fromthe following components:

1,3 bis(beta-ethy1hexyl) 5 methyl 5 -amino hexahydro-pyrimidine g Whiteointment (USP), q. s. to 100.0 g.

Example 17 A therapeutic ophthalmic ointment was prepared from thefollowing components:

G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrirnidine 0.10Mineral oil 8.50 Wool fat 9.15

Petrolatum, q. s. to 100.00 g.

Example 18 A therapeutic nasal drop composition was prepared from thefollowing components:

G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1Complex sorbitol ether-ester dispersing agent (sold under the tradedesignation Tween 20) 1.4 Sodium chloride 0.9

Distilled water, q. s. to 100.00 ml.

Example 19 A therapeutic nasal spray was prepared from the followingcomponents:

1,3 bis(beta-ethylhexyl) 5 methyl 5 -ami.no-

hexahydro-pyrirnidine 0.1 Menthol 0.5

Light mineral oil (US P), q. s. to 100.0 ml.

Example 20 Atherapeutic nasal jelly was prepared from the followingcomponents:

G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1

8 Glycerine Tragacanth Distilled water, q. s. to 100.0 g.

Example 21 A therapeutic vaginal insulfiation powder was prepared fromthe following components:

1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1 Boricacid 5.0 Lactose 20.0

Kaolin, q. s. to 100.0 g.

Example 22 A therapeutic vaginal tablet was prepared from the followingcomponents:

a G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.01Boric acid 0.50

Lactose 0.50

Example 23 The therapeutic vaginal suppository was prepared from thefollowing components:

1,3 bis (beta ethylhexyl) 5 methyl 5 aminohexahydropyrimidine 0.01Glycerinated gelatin base 10.00

The suppository was prepared in accordance with the procedure set forthon page 764 of the United States Pharmacopeia (fourteenth revision).

Example 24 A therapeutic scalp lotion was prepared from the followingcomponents:

1,3 bis (beta ethylhexyl) 5 methyl 5 aminohexahydropyrimidine g 0.1Ethyl alcohol ml 65.0

- Distilled water, q. s. to 100.0 m1.

Example 25 A therapeutic soap was prepared by compressing the followingcomponents into soap cakes:

1,3 bis(beta-ethylhexyl) 5 methyl 5 aminohexahydropyrimidine g.. 0.2Soap granules (Ivory"), q. s. to 100.0 g.

Other compositions of the invention analogous to the above-describedcompositions and containing comparable amounts of the pyrimidinecompounds specifically enumerated above may be prepared and areeffective in the practice of the invention.

Example 26 A therapeutic foot powder was prepared from the followingcomponents:

Components: Parts by weight, g.

1,3 bistbeta ethylhexyl) 5 methyl 5- amino-hexahydropyrimidinesalicylate 0.142

Boric acid 10.0

Starch 20.0

Talc, q. s. to 100.0 g.

The trihydrochloride is also useful in this composition.

Example 27 A therapeutic throat lozenge is prepared by subjecting amixture of the following components to compression molding, the amountsgiven being suflicient for the preparation of 1000 tablets weighing onegram each:

Components: Parts by weight, g.

1,3 bis(beta ethylhexyl) methyl 5- amino hexahydropyrimidinetrihydrochloride 1.5 Benzocaine 5.0 Sodium citrate 10.0 Syntheticsweetener (sodium saccharin and sodium cyclamate) 10.5 Sugar, powdered656.0 Magnesium stearate 5.0 Flavor 4.5 Color 0.05 Polyethylene glycol6000, q. s. to 1000.0 g.

Example 28 A therapeutic vaginal gel is prepared from the followingcomponents:

Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5-amino-hexahydropyrimidine g 1.00 Lactic acid, U. S. P. cc 2.50Polysorbate 80 (polyoxyethylene sorbitan monooleate) g 14.00Polyethylene glycol 400 g 50.00 Sodium carboxymethyl cellulose g 20.00Sodium chloride g 8.00 Sodium benzoate g 3.00

Water, potable, q. s. to 1000.00 cc.

The lactic acid present is in stoichiometric excess to form the lactateof the amine base.

Example 29 A therapeutic vaginal gel preparation is formulated bycombining the following:

Components: Parts by weight, g.

1,3 bis(beta ethylhexyl) 5 methyl 5- amino hexahydropyrimidinetrihydrochloride 1.33 Polyethylene glycol 400 50.00 Sodium carboxymethylcellulose (type 70 HV) 20.00 Sodium chloride 8.00 Sodium benzoate 3.00

Water, potable, q. s. to 1000.00 ml.

Example 30 A therapeutic shampoo is prepared from the followincomponents:

Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5-Diethanolamine amide of lauric acid kg 3.000 Hydrochloric acid (20%w./v.) 1iters 1.800 Formaldehyde solution, U. S. P. do Water, potable,q. s. to 100.000 liters.

Example 31 An antifugal nail preparation is formulated from thefollowing:

Components: Parts by weight, g.

1,3 bis (beta ethylhexyl) 5 methyl 5 amino hexahydropyrimidinesalicylate n 5 hydroxide.

'10 Polysorbate 15 Sodium carboxymethyl cellulose 10 Sodium benzoate 3Water, q. s. to 1000 cc.

Example 32 'A non-water washable ointment was prepared from thefollowing components:

Components: Parts by weight, g.1,3-bis(beta-ethylhexyl)-5-methyl-5-amino hexahydropyrimidine valerate0.1

Benzocaine 0.5

Petrolatum, U. S. P., q. s. to 100.0 g.

The above ointment can be converted to a water washable ointment bysubstituting hydrophilic ointment, U. S. P., in place of the petrolatum.

Example 33 A therapeutic suspension of the trihydrochloride of 1,3bis(beta ethylhexyl) 5 methyl 5 amino hexahydropyrirnidine is obtainedby adding 6.5 g. of the trihydrochloride salt to 15 cc. of distilledwater, adding the solution obtained to a solution of 40 g. ofpolyvinylpyrrolidone in 40 cc. of distilled water, adjusting the pH to6.8-7.2 by adding aqueous 30% sodium hydroxide solution, then adding asolution of 20 g. of sodium carboxymethyl cellulose in 600 cc. ofdistilled water and finally bringing the total volume to 1000 ml. byadding the'necessary amount of distilled water.

Example 34 A mouthwash was prepared from the following components:

A therapeutic shampoo is obtained by combining the following components:

Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5- aminohexahydropyrimidine trihydrochloride 3 1.33 Distearate of polyethyleneglycol 400 g 16.7 Ammonium lauryl sulfate (27% solution) g 500.0Distilled water cc 20.0 Ethyl alcohol, q. s. to cc 1000.00 Perfume cc1.8

The pH is adjusted to 6.5 with aqueous 10% sodium Example 36 Atherapeutic vaginal suppository was prepared by molding a mixture of thefollowing components into suppositories weighing one gram, each:

Components: Parts by weight, g.

1,3 bis(beta ethylhexyl) 5 methyl 5- amino-hexahydropyrimidinetrihydrochloride 1.50 Gramicidin 0.05 Neomycin sulfate 1.00 Polyethyleneglycol 6000..- 650.0

Beta-lactose 430.0

"11 Example 37 A dentrifice composition was prepared from the followingcomponents:

Components: Percent by weight Alumina hydrate 40.0 Titanium dioxide 1.0Sodium saccharin 0.15 Detergent 3.0 Gum tragacanth 1.5 Sodium oxalate0.5 Glycerine 12.0 d-Sorbitol solution 17.0 Phosphoric acid 85% 0.3Flavor 0.986

1,3 bis(beta ethylhexyl) methyl 5- amino-hexahydropyrimidinetrihydrochloride 0.283 Complex sorbitol ether-ester dispersing agent(sold under the trade designation Tween 20) 0.0667 Water (q. s. to 100%)23.214

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above products without departingfrom the scope of the invention, it is intended that all mattercontained in the above description shall be interpreted as illustrativeand not in a limiting sense.

We claim:

1. A therapeutic composition effective to'inhibit the growth ofmicroorganisms, free of undesirable toxic effects, comprising apharmaceutical carrier and a substantial amount, less than 1% by weight,of a compound of the group consisting of those having the formula:

wherein R represents a radical selected from the group consisting ofalkyl, aryl, aralkyl, alkaryl, hydroxy-alkyl, aminoalkyl, and cycloalkyland R is selected from the group consisting of hydrogen, lower alkyl andhydroxymethyl radicals and the salts of said compounds.

2. The composition set forth in claim 1 wherein the compound isl,3-bis(1-methyl heptyD-S-methyl-S-amino- 5-aminohexahydropyrimidine.

3. The composition set forth in claim 1 wherein the compound is1,3-bis(beta ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.

4. The composition set forth in claim 1 wherein the compound is1,3-bis(1-methyl heptyD-S-methyl-S- aminohexahydropyrimidine.

5. The composition set forth in claim 1 wherein the compound is1,3-bisheptyl-5-methyl-5-amino-hexahydropyrimidine.

6. The composition set forth in claim 1 wherein the compound is1,3-bisoctyl-5-methyl-S-amino-hexahydropyrimidine.

7. The composition set forth in claim 1 wherein the compound is 1,3bis(methyl-benzyl)-5-m thyl-i-atninc hexahydropyrimidine.

8. A dental composition comprising a tooth cleaning component and asubstantial amount, less than 1% by weight, of1,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.

9. A dental composition comprising a tooth cleaning component and asubstantal amount, less than 1% by weight, of a salt of1,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.

10. A mouthwash composition comprising an aqueous alcoholic vehicle anda substantial amount, less than 1% by weight, ofl,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.

11. A mouthwash composition comprising an aqueous alcoholic vehicle anda substantial amount, less than 1% by weight, of a salt of1,3-bis(beta-ethylhexyU-S- methyl-5-amino-hexahydropyrimidine.

12. A water-washable ointment comprising a hydrophilic ointment base anda substantial amount, less than 1% by weight, of1,3-bis(beta-ethylhexyl)-S-methyl- 5-amino-hexahydropyrimidine.

13. A water-washable ointment comprising a hydro philic ointment baseand a substantial amount, less than 1% by weight, of a salt of1,3-bis(beta-cthylhexyD-S- methyl-S-amino-hexahydropyrimidine.

14. A vaginal suppository comprising a glycerinated gelatin base and asubstantial amount, less than 1% by weight, ofl,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.

15. A soap composition comprising a soap base and a substantial amount,less than 1% by weight, of 1.3- bis(beta ethylhexyl) 5 methyl 5 aminohexahydropyrimidine.

16. The method of treating humans and animals to inhibit the growth ofmicroorganisms which comprises topically administering to said humansand animals a composition of claim 1.

17. The method of treating humans and animals to inhibit the growth ofmicroorganisms which comprises systemically administering to said humansand animals a composition of claim 1. I

18. The method of treating humans and animals to inhibit the growth ofmicroorganisms which comprises topically administering to said humansand animals -a composition of claim 2.

19. The method of treating humans and animals to inhibit the growth ofmicroorganisms which comprises systemically administering to said humansand animals a composition of claim 2.

20. The method. of treating humans and animals to inhibit the growth ofmicroorganisms which comprises topically administering to said humansand animals a composition of claim 3.

21. The method of treating humans and animals to inhibit the growth ofmicroorganisms which comprises systemically administering to said humansand animals a composition of claim 3.

OTHER REFERENCES Fosdick et al.: J. D. R., vol. 32, No. 4, August 1953,pp. 486-496.

1. A THERAPEUTIC COMPOSITION EFFECTIVE TO INHIBIT THE GROWTH OFMICROORGANISMS, FREE OF UNDESIRABLE TOXIC EFFECTS, COMPRISING APHARMACEUTICAL CARRIER AND A SUBSTANTIAL AMOUNT, LESS THAN 1% BY WEIGHT,OF A COMPOUND OF THE GROUP CONSISTING OF THOSE HAVING THE FORMULA: